Traumatic brain injury (TBI) causes neuronal cell death, combined with astroglial proliferation and inflammation associated with the activation of microglia, which contributes to irreversible tissue damage. Such secondary injury begins within seconds to minutes after the insult and may continue for days, weeks and potentially even months to years. Recent evidence from our laboratory shows chronic inflammation in the CNS lasting at least 6 months after injury. Inflammation may contribute to chronic neurodegeneration after trauma as well as to disorders such as Alzheimer's disease (AD) or Parkinson's syndrome. Pilot studies in our laboratory have indicated that inflammation may be inhibited by activation of mGluR5 receptors in microglia. Furthermore, our data suggest that mGluR5 effects may be mediated by actions on the NADPH oxidase enzyme, which functions to produce reactive oxygen species (ROS) by microglia and may play a significant role in persistent activation of microglia following injury. The proposed studies are intended to address the following hypotheses: (1) NADPH oxidase inhibition reduces microglial activation, production of pro-inflammatory factors and associated neurological dysfunction after TBI; (2) mGluR5 stimulation attenuates microglia activation and secondary neuronal cell death, and improves functional outcomes after TBI; (3) mGluR5, but not mGluR1, modulates microglial activation and neurotoxicity in primary microglia cultures, a microglial cell line, and microglia/neuronal co-cultures, in part through inhibition of NADPH oxidase; and (4) the G1q-protein signal transduction pathway is the critical component of the mGluR5 signal transduction events leading to inhibition of microglial NADPH oxidase and suppression of microglial activation. Specific aims are to demonstrate: (1) the importance of NADPH oxidase in microglial activation and correlated production of pro-inflammatory factors in the chronic neuronal cell loss and associated neurological dysfunction after TBI; (2) that mGluR5 stimulation attenuates microglial activation, decreases neuronal cell death and improves functional outcomes after TBI in contrast to mGluR5 global knockout animals that show greater microglial activation and neuronal cell death. We will also distinguish the relative roles of microglial versus neuronal mGluR5 using conditional/inducible knockout mice; (3) that mGluR5, but not mGluR1, modulates microglial activation and neurotoxicity in multiple cell culture models of microglial stimulation; and (4) that the G1q-protein signal transduction pathway is initiated by mGluR5 stimulation and is critical for attenuation of microglial activity by preventing activation of the NADPH oxidase enzyme complex, using in vitro microglial cell models.